Clopidogrel May Be Less Help in Diabetic Heart

Action Points

A Danish observational study found decreased effectiveness of clopidogrel in diabetics following a myocardial infarction compared with nondiabetics.

Note that all-cause mortality was less decreased and cardiovascular mortality was not significantly reduced in the diabetics compared with nondiabetics.

Patients with diabetes may not get as much benefit from clopidogrel (Plavix) for secondary prevention after a heart attack as nondiabetic patients, a Danish registry study showed.

Compared with other clopidogrel users, diabetes patients saw less of a reduction in all-cause mortality, with hazard ratios of 0.89 versus 0.75 (P<0.001 for interaction), Charlotte Andersson, MD, PhD, of Gentofte Hospital in Hellerup, Denmark, and colleagues found.

The group with diabetes also lost the substantial effect on cardiovascular mortality seen in those without diabetes, the group reported in the Sept. 5 issue of the Journal of the American Medical Association.

In the population-based study, diabetes patients achieved a nonsignificant 7% reduction in risk of death from cardiovascular causes compared with the significant 23% reduction seen among other clopidogrel users (P=0.01 for interaction).

Clopidogrel may still be worthwhile for diabetes patients, given their higher absolute risks of events, Andersson's group noted.

"Available data nevertheless raise a possibility that patients with diabetes may benefit from a more potent platelet inhibitor strategy to achieve a relative risk reduction similar to patients without diabetes," they wrote.

Other drugs, such as prasugrel (Effient) and ticagrelor (Brilinta), are stronger inhibitors of the P2Y12 pathway that leads to platelet activation.

Clopidogrel also targets that pathway but often doesn't do enough to quell the heightened P2Y12 activity in diabetes, based on platelet reactivity assay results.

The more potent agents have been shown more effective than clopidogrel in the PLATO and TRITON-TIMI 38 trials, and sub-analyses have indicated larger absolute benefits with no increased bleeding risk in the diabetes subgroup, Deepak Bhatt, MD, MPH, of Brigham and Women's Hospital and the VA Boston Healthcare System, noted in an accompanying editorial.

"It's not that clopidogrel doesn't work in this situation," he said in an interview with MedPage Today. "Can we do better is the possibility this paper raises and...the answer is likely yes."

Bhatt warned against relying on nonrandomized comparisons, as in the current study, which looked at individual-level data on 58,851 patients who survived at least 30 days after an acute myocardial infarction (MI) without coronary artery bypass graft (CABG) surgery. All patients were hospitalized with incident MI between 2002 and 2009 and were listed in the Danish National Patient Register. Follow-up was done for 1 year.

CABG patients were excluded because they are likely to stop clopidogrel treatment after surgery, the authors explained.

Notably, the 12% with diabetes seemed to derive significantly less benefit from clopidogrel versus no clopidogrel for the composite endpoint of recurrent MI and all-cause mortality (HR 1.00 versus 0.91, P=0.08 for interaction)

Also, among those who underwent percutaneous coronary intervention (PCI), clopidogrel appeared similarly beneficial for all the endpoints regardless of diabetes status.

Because the majority of patients did undergo PCI, that finding "to an extent, undercuts the authors' hypothesis of differential benefit," Bhatt wrote in the editorial.

The researchers acknowledged the possibility of unmeasured confounding, particularly confounding by indication.

Propensity score-matched results paralleled those of the main findings, but no data were available on smoking status, stents used, body mass index, ejection fraction, and certain other factors.

European guidelines recommend ticagrelor or prasugrel over clopidogrel in acute coronary syndromes; U.S. guidelines suggest use of clopidogrel or prasugrel without distinction, because the increased bleeding risk with the more potent anti-platelet agent may offset its benefits.

Guidelines are unlikely to change based on an observational analysis like this one, Bhatt noted.

However, another clinical trial -- PEGASUS-TIMI 54 -- is comparing ticagrelor versus placebo atop aspirin after MI and should give another chance to look for any specific interaction with diabetes, he pointed out.

Andersson reported receiving a month's salary for work on the study. Coauthors reported conflicts of interest with Bristol-Myers Squibb, Cardiome, Merck, Sanofi, and Servier.

Bhatt reported relationships with Medscape Cardiology, the Society of Chest Pain Centers, PEGASUS-TIMI 54, the CHARISMA and TRILOGY trials, the American Heart Association Get With The Guidelines Science Subcommittee, the American College of Cardiology, Duke Clinical Research Institute, Slack Publications, WebMD, and the Journal of Invasive Cardiology. He reported grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, sanofi-aventis, and The Medicines Company as well as unfunded research for FlowCo, PLx Pharma, and Takeda.

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